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Independent Human Prostate Cancer Cell Lines

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Independent Human Prostate Cancer Cell Lines [CANCER RESEARCH 62, 5365–5369, September 15, 2002] Raloxifene, a Mixed Estrogen Agonist/Antagonist, Induces Apoptosis in Androgen- independent Human Prostate Cancer Cell Lines Isaac Yi Kim, Byung-Chul Kim, Do Hwan Seong, Dug Keun Lee, Jeong-Meen Seo, Young Jin Hong, Heung-Tae Kim, Ronald A. Morton, and Seong-Jin Kim1 Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892 [I. Y. K., B. C. K., D. H. S., D. K. L., J-M. S., H-T. K., S-J. K.]; Scott Department of Urology, Baylor College of Medicine, Houston, Texas 77030 [I. Y. K., R. A. M.]; and Clinical Research Center, College of Medicine, Inha University, Inchon, South Korea 400-711 [Y. J. H.] ABSTRACT metastasis. After androgen withdrawal, there is a dramatic decrease in PSA with improvement in clinical parameters. However, prostate Raloxifene, a selective estrogen receptor (ER) modulator, is a mixed cancer cells inevitably become resistant to the androgen-withdrawal estrogen agonist/antagonist that has been shown to prevent osteoporosis therapy with a median time of 18–24 months (5). Once the hormone and breast cancer in women. Because the prostate contains high levels of ER-␤, the present study investigated the effect of raloxifene in three refractory prostate cancer emerges, treatment is largely limited to well-characterized, androgen-independent human prostate cancer cell palliative care. lines: (a) PC3; (b) PC3M; and (c) DU145. Reverse transcriptase-PCR and Raloxifene is the prototypical SERM that has been shown to Western blot analysis for ER-␣ and ER-␤ demonstrated that all three cell prevent osteoporosis and breast cancer (6, 7); other well-known mem- lines express ER-␤, whereas only PC3 and PC3M cells were positive for bers of SERMs include tamoxifene, droloxifene, and idoxifene. ER-␣. After the treatment with raloxifene, a dramatic increase in cell SERMs are synthetic estrogen ligands that can exhibit either an death was observed in a dose-dependent manner in the three prostate estrogenic or an antiestrogenic effect depending on the tissue types ؊9 ؊6 cancer cell lines (10 to 10 M range). Because the three prostate cancer (reviewed in Refs. 8 and 9). Specifically, SERMs are usually ER cell lines demonstrated similar morphological changes after the raloxifene agonists in bone, liver, and cardiovascular system; ER antagonists in treatment, PC3 (ER-␣/ER-␤؉) and DU145 (ER-␤؉ only) cells were brain and breast; and mixed ER agonists/antagonists in the uterus selected to further characterize the raloxifene-induced cell death. Using the nucleus-specific stain 4؅,6-diamidino-2-phenylindole, nuclear frag- (reviewed in Refs. 8 and 9). Published works have demonstrated that ␣ ␤ mentation was observed in a time-dependent manner in both cell lines raloxifene binds to both ER- and ER- with high affinity (10, 11); ␤ ␣ ؊6 after exposure to 10 M raloxifene. Using the terminal deoxynucleotidyl however, the binding affinity to ER- is four times higher than ER- . transferase-mediated nick end labeling apoptotic assay, it was demon- Among the SERMs, raloxifene is unique in that it is an estrogen strated that the nuclear fragmentation was caused by apoptosis. To in- antagonist in the uterus (12). In the breast and bone, although, all vestigate the possibility that caspase activation is involved in raloxifene- SERMs act as estrogen antagonists and agonists, respectively (13). induced apoptosis, cells were treated with the pan-caspase inhibitor The mechanism for the observed tissue-specific effect of SERMs has ZVAD. The results demonstrated that the dramatic change in cellular been shown recently to be attributable to differences in coregulator morphology after treatment with raloxifene was no longer observed when recruitment in a tissue-specific manner (14). cells were pretreated with ZVAD. Immunoblot demonstrated activation of Since the discovery of ER-␤ from the rat prostate cDNA library caspases 8 and 9 in PC3 and DU145 cells, respectively. Taken together, these results demonstrate that the mixed estrogen agonist/antagonist, (15), series of evidence have suggested an important role for estro- raloxifene, induces apoptosis in androgen-independent human prostate gen/ER in the prostate: (a) in the rat prostate, immunohistochemistry cancer cell lines. has demonstrated that ER-␣ is present in the stroma, whereas ER-␤ is localized preferentially in the epithelium (16); (b) increased expres- INTRODUCTION sion of ER-␣ has been associated with prostate cancer progression, metastasis, and hormone-refractory phenotype (17); (c) a recent Phase In the United States, prostate cancer is the most common malig- II clinical trial using the estrogen agonist diethylstilbestrol in nancy and the second leading cause of male cancer deaths (1). Since hormone-refractory prostate cancer demonstrated Ͼ50% decrease in 2 the widespread implementation of PSA for prostate cancer screening the level of PSA in 43% of the patients (18); and (d) ER-␤ knockout in the late 1980s, the incidence of nonorgan-confined prostate cancer mice exhibit prostate and bladder hyperplasia (19). These observa- has decreased dramatically (2). Nevertheless, ϳ30% of prostate can- tions, taken together, suggest that ER is a reasonable target for cer patients who undergo radical prostatectomy or radiotherapy for therapeutic intervention in prostate cancer patients. Therefore, the clinically localized disease go on to develop either a local or distant present study examined the effect of raloxifene in androgen-indepen- relapse (3, 4). Once prostate cancer recurs after the definitive treat- dent human prostate cancer cell lines. We report that raloxifene ment for a localized disease, the most widely used treatment is either induced apoptosis in androgen-independent human prostate cancer a medical or a surgical androgen withdrawal; chemotherapy has been cells. shown to be largely ineffective in treating prostate cancer. In addition to patients with recurrence, androgen ablation is also the treatment of MATERIALS AND METHODS choice for those who present with extensive local invasion or distant Cell Culture and Mitogenic Assay. Human prostate (PC3 and DU145) Received 3/20/02; accepted 7/11/02. and breast (MCF-7, ZR-75–1, and HS-578T) cancer cell lines were purchased The costs of publication of this article were defrayed in part by the payment of page from American Type Culture Collection (Rockville, MD). PC3M cells were charges. This article must therefore be hereby marked advertisement in accordance with kindly provided by Dr. Jane Trepel (National Cancer Institute, NIH). All cells 18 U.S.C. Section 1734 solely to indicate this fact. used in this study were from 35th through 40th passages. Cells were routinely 1 To whom requests for reprints should be addressed, at Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Building 41, Rm C629, 9000 Rockville maintained in RPMI 1640 containing 10% FBS, penicillin (100 units/ml), and Pike, Bethesda, MD 20892. Phone: (301) 496-8350; Fax: (301) 496-8395; E-mail: streptomycin (100 ␮g/ml). Raloxifene (Eli-Lily, Indianapolis, IN) was diluted Ϫ [email protected]. to 10 2 M in 70% ethanol and added to the culture medium at selected 2 The abbreviations used are: PSA, prostate-specific antigen; ER, estrogen receptor; concentrations. RT-PCR, reverse transcription-PCR; DAPI, 4Ј,6-diamidino-2-phenylindole; FBS, fetal bovine serum; TUNEL, terminal deoxynucleotidyl transferase-mediated nick end labeling; For cell counts, cells were plated at 20,000/well in 24-well culture plates in TBS, Tris-buffered saline; SERM, selective estrogen receptor modulator. RPMI 1640 supplemented with 10% FBS and allowed to adhere for 24 h. Then 5365 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2002 American Association for Cancer Research. RALOXIFENE INDUCES APOPTOSIS IN PROSTATE CANCER CELLS the cultures were washed two times with PBS, and the cells from wells selected membranes were incubated in the presence of rabbit-antimouse secondary previously were counted to determine the plating efficiency. Cells in the antibody (Pierce Chemical Co., Rockford, IL) at a dilution of 1:3000 for 2 h. remaining wells were cultured for 4 days in phenol red-free RPMI 1640 After washing several times with TBST, immunoreactive bands were visual- supplemented with 1% charcoal-stripped FBS containing raloxifene at 0, ized by enhanced chemiluminescence. Ϫ Ϫ Ϫ Ϫ Ϫ 10 11,10 9,10 7,10 6, and 10 5 M. Raloxifene was added such that the ratio TUNEL and ZVAD Treatment. Cells were plated on chamber slides and of 70% ethanol to the culture medium was 1:1000. For control, 70% ethanol incubated 24 h before treatment with raloxifene. After exposure to raloxifene was added to culture at 1:1000. The medium was changed at day 2. After for a designated amount of time, cells were fixed in 4% paraformaldehyde removing the medium and detaching the cells with 0.5 ml of 0.05% trypsin, (pH 7.4) for 10 min. TUNEL assay of fragmented DNA was performed as cells were counted using hemocytometer. Photomicrographs were taken to recommended by the manufacturer (Roche Molecular Biochemicals, Indian- document the changes in cellular morphology. All experiments were repeated apolis, IN). three times, and similar results were obtained each time. ZVAD (Roche Molecular Biochemicals) was dissolved in DMSO to a RNA Isolation and RT-PCR. RT-PCR for ER-␣ and ER-␤ was carried concentration of 50 mM. Then it was added to medium at 50 ␮M 30 min before out as described previously (17). Cells were harvested, and total RNA was treatment with raloxifene. As control, DMSO was added to the culture medium isolated using TRIzol reagent (Life Technologies, Inc., Grand Island, NY), at 1:1000. Cells were observed for 48 h, and photomicrographs were taken to according to the manufacturer’s protocol. Once isolated, total RNA was document the changes in cellular morphology. reverse transcribed using Superscript (Life Technologies, Inc.) and random Statistics. All numerical data are expressed as mean Ϯ SE with triplicate hexamer using the following conditions: 42°C for 50 min and 70°C for 15 min.
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